Grading of Recommendations Assessment, Development and Evaluation (GRADE) of a 2-dose 

schedule for human papillomavirus (HPV) vaccination

Introduction 

Three HPV vaccines are licensed for use in the United States as a 3-dose series: quadrivalent and 9-valent

HPV vaccines (4vHPV and 9vHPV, Gardasil and Gardasil 9, Merck and Co, Inc., Whitehouse Station, 

NJ)(1, 2) and bivalent HPV vaccine (2vHPV, Cervarix, GlaxoSmithKline, Rixensart, Belgium).(3) In 

October 2016, 9vHPV was approved for use in a 2-dose series for girls and boys initiating the vaccination 

series at ages 9 through 14 years. Grading of Recommendations Assessment, Development and 

Evaluation (GRADE) was adopted by the Advisory Committee on Immunization Practices (ACIP) in 

2011,(4) and a 2-dose schedule for HPV vaccine was considered using GRADE. The main policy 

question was, “Should 2 doses of any HPV vaccine given 6–12 months apart be recommended routinely 

for 9 through 14 year-olds?” Factors considered in determining the recommendation included benefits and 

harm, GRADE evidence type, values and preferences, and health economic analyses. 

Methods for GRADE

Scientific literature was searched from January 2006 through June 2016 using the PubMed database and 

ClinicalTrials.gov. The medical subject headings (MeSH) searched were Papillomavirus Vaccines, 

including all subheadings, with no limitations except human subjects. Text word searches were performed 

on additional terms, including HPV vaccine, impact, effective, dose, and doses. Studies were included if 

the population was adolescents (any gender) aged 9–14 years; intervention was administration of 2 doses 

of any HPV vaccine separated by 6 or more months (±4 weeks); comparison was 3 doses of HPV vaccine 

among young adults within the age group (15–26 years) in which efficacy was demonstrated in clinical 

trials; and outcomes were primary data on HPV-associated health outcomes. 

The draft policy note based on the ACIP recommendation was shared with ACIP voting members and 

revisions were made based in part on their feedback. The CDC Director approved a decision memo 

outlining the recommendation prior to publication of the policy note. The opinions of individual members 

of ACIP might not be fully reflected in this document, as the guideline represents the position of CDC 

based on the ACIP recommendation to the CDC director and is not a consensus document. The Work 

Group continues to review data as they become available, and considers any needed policy changes.

1 

https://www.cdc.gov/vaccines/acip/recs/grade/hpv-2-dose.pdf 3/12/2019
Results

Benefits considered critical outcomes in GRADE were prevention of cervical precancers and cancers, 

oropharyngeal cancer, anal cancer, vaginal/vulvar cancer, and penile cancers (Table 1). Additional 

important outcomes included HPV infections and anogenital warts/condyloma. Immunogenicity was 

considered a surrogate marker for prevention of important and critical outcomes, when immunobridging 

studies were available comparing immunogenicity in the group of interest (i.e., boys or girls aged 9 

through 14 years) with a comparison group in which efficacy has been demonstrated in clinical trials (i.e., 

women aged 15 or 16 through 26 years). 

For 9vHPV, one immunobridging study was identified that was also the basis of the FDA decision on 2-

dose approval;(5) for 4vHPV, two immunobridging studies were identified;(6, 7) and for 2vHPV, four 

immunogenicity studies were identified (Table 2).(8-11) Included data showed high seroconversion rates 

among all cohorts and non-inferior geometric mean antibody titers (GMTs) for all HPV vaccine types in 

boys and girls receiving 2-dose schedules compared with groups in which efficacy was demonstrated in 

clinical trials. (Table 3). These studies received a final GRADE evidence type of 3. (Table 4) Same-age 

comparisons of seroconversion rates and GMTs among boys and girls receiving a 2-dose schedule 

compared with a 3-dose schedule were not included in GRADE but are shown as supplemental data 

(Table 5). 

Overall GRADE evidence type was 3 (Table 6). Favorable safety profiles for HPV vaccines have been 

well-established,(12, 13) and no data suggest that adverse events increase with a 2-dose schedule 

compared with a 3-dose schedule. When benefits are similar and potential for adverse events is lower, 

then the balance of benefits over harms is greater.

Considerations for formulating recommendations for a 2-dose schedule of HPV vaccine included the 

following key factors: balance of benefits over harms, GRADE evidence type, values and preferences, 

and cost-effectiveness considerations (Table 7). 

2 
Table 1. Important and critical outcomes related to HPV vaccination

Outcome Importance Included in 

evidence profile

Benefits

Immunogenicity 

(Seroconversion / Geometric Mean Titers / Avidity)

Important Yes

HPV infections Important No*

Anogenital warts/condyloma Important No*

Cervical precancer 

(Cervical intraepithelial neoplasia [CIN] 2/3 or 

adenocarcinoma in situ [AIS] 2/3)

Critical No†

Cervical cancer Critical No†

Oropharyngeal cancer Critical No†

Anal cancer Critical No†

Vaginal/vulvar cancer Critical No†

Penile cancer Critical No†

* No data available for dosing interval or age range specified in policy question

† No data available on these HPV-associated outcomes

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Table 2. Characteristics of included studies

Vaccine Author, year

(reference)

Study design

(N=total enrolled) Participants

Number of HPV 

vaccine doses 

(dosing schedule)

Main outcomes

9vHPV Iversen, 

2016(5)

Immunobridging 

study, 15 countries

(N=1518)a

Girls, age 9–14 years,

Boys, age 9–14 years,

Women, age 16–26 years

2 doses (M 0, 6)

2 doses (M 0, 12)

3 doses (M 0, 2, 6)

Immunogenicity 

(seroconversion and GMTs)

4vHPV

Dobson, 

2013(6)

Immunobridging 

study, Canada

(N=830)b

Girls age 9–13 years,

Women age 16–26 years

2 doses (M 0,6)

3 doses (M 0, 2, 6)

Immunogenicity 

(seroconversion and GMTs)

HernándezÁvila, 

2016(7)

Immunobridging 

study, Mexico

(N=450)c

Girls age 9–10 years, 

Women age 18–24 years

2 doses (M 0, 6) 

3 doses (M 0, 2, 6)

Immunogenicity 

(seroconversion and GMTs)

2vHPV

Romanowski, 

2016(8)

Immunobridging 

study, Canada and 

Germany (N=961)d

Girls age 9–14 years,

Women age 15–25 years

2 doses (M 0, 6)

3 doses (M 0, 1, 6)

Immunogenicity 

(seroconversion and GMTs)

Puthanakit, 

2016(9)

Immunobridging 

study, Canada, 

Germany, Italy, 

Taiwan, Thailand

(N=1447)e

Girls age 9–14 years,

Women age 15–25 years

2 doses (M 0, 6)

2 doses (M 0, 12)

3 doses (M 0, 1, 6)

Immunogenicity 

(seroconversion and GMTs)

LazcanoPonce, 

2014(10)

Immunobridging 

study, Mexico

(N=2000)f

Girls age 9–10 years, 

Women age 18–24 years

2 doses (M 0, 6)

3 doses (M 0, 1, 6)

Immunogenicity 

(seroconversion and GMTs)

Boxus, 

2014(11)

Observational

(N=203 specimens 

from 180 

individuals)g

Girls age 10–14 years, 

Women age ≥15 years

2 doses (M 0, 6)

3 doses (M 0, 1, 6)

Immunogenicity 

(avidity)

4
a NCT 1984697, funded by Merck; results presented publicly at ACIP in February 2016 b NCT 00501137, funded by Ministries of Health in British Columbia, Nova Scotia, and Quebec (Laboratory testing: Merck) c NCT 01717118, funded by Ministry of Health in Mexico and National Institute of Public Health in Mexico (Laboratory testing: Merck) d NCT 00541970, funded by GlaxoSmithKline e NCT 01381575, funded by GlaxoSmithKline f NCT 01717118, funded by Ministry of Health in Mexico (Laboratory testing: GlaxoSmithKline) g Specimens from NCT 00541970, NCT 00196924, NCT 00196937, funded by GlaxoSmithKline

GMTs, Geometric Mean Titers; M, months after dose 1; NCT, National Clinical Trial number

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Table 3. Included data, immunogenicity

Vaccine Outcome

Number of 

subjects 

(number 

of studies)

Comparison groups Benefits

9vHPV

Immunogenicity 

(seroconversion to 

9vHPV types)

1102 (1)

Girls and boys 

2 doses (M 0, 6) and 

Girls and boys 

3 doses (M 0, 12) and

Women 

3 doses (M 0, 2, 6)

≥97.9% seropositive at 1 month post last dose in 

all groups in the per-protocol population

Immunogenicity 

(GMTs for 

9vHPV types)

560 (1)

Girls 

2 doses (M 0,6) versus

Women 

3 doses (M 0, 2, 6)

Non-inferiority criteria met for all 9vHPV types at 

1 month post last dose

559 (1)

Boys 

2 doses (M 0, 6) versus

Women 

3 doses (M 0, 2, 6)

Non-inferiority criteria met for all 9vHPV types at 

1 month post last dose

555 (1)

Girls and boys 

2 doses (M 0, 12) versus

Women 

3 doses (M 0, 2, 6)

Non-inferiority criteria met for all 9vHPV types at 

1 month post last dose

4vHPV

Immunogenicity 

(seroconversion to 

4vHPV types)

806 (2)

Girls 

2 doses (M 0,6) and

Women 

3 doses (M 0, 2, 6)

≥97.1% seropositive at 1 month post last dose in 

all groups in the per-protocol population

Immunogenicity 

(GMTs for 

4vHPV types)

806 (2)

Girls 

2 doses (M 0, 6) versus

Women 

3 doses (M 0, 2, 6)

Non-inferiority criteria met for all 4vHPV types

at 1 month post last dose and later (latest M 36)

2vHPV

Immunogenicity 

(seroconversion to 

2vHPV types)

2840 (3)

Girls 

2 doses (M 0, 6 or 12) and

Women 

3 doses (M 0, 1, 6)

100% seropositive at 1 month post last dose in all 

groups in the per-protocol population

Immunogenicity 

(GMTs for 

2vHPV types)

2840 (3)

Girls 

2 doses (M 0, 6 or 12) 

versus

Women 

3 doses (M 0, 1, 6)

Non-inferiority criteria met for both 2vHPV types

at 1 month post last dose and later (latest M 60)

Immunogenicity 

(antibody avidity 

for 2vHPV types)

180 (1)

Girls 

2 doses (M 0, 6) and

Women 

3 doses (M 0, 1, 6)

No differences in avidity index, suggesting similar 

quality of antibody response at M 7, 24, and 48

in 2-dose versus 3-dose recipients

GMTs, Geometric Mean Titers; M, months after dose 1

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Table 4. Type of evidence

Vaccine Finding

Design 

(number 

of studies)

Initial 

evidence 

level

Risk of bias Inconsistency Indirectness Imprecision

Other 

considerationsa

Evidence 

type

9vHPV

Non-inferior 

immunogenicity, 

9vHPV types

Obs (1) 3 No serious No serious No seriousb No serious None 3

4vHPV

Non-inferior 

immunogenicity, 

4vHPV types

Obs (2) 3 No serious No serious No seriousb No serious None 3

2vHPV

Non-inferior 

immunogenicity, 

2vHPV types

Obs (4) 3 No serious No serious No seriousb No serious None 3

a Strength of association, dose-response, plausible residual confounding, publication bias b Not downgraded for indirectness since immunobridging studies use a comparison group in which clinical efficacy has been established

Obs, Observational

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Table 5. Supplemental data, immunogenicity

Vaccine Outcome

Number of 

subjects 

(number 

of studies)

Comparison groups Benefits

9vHPV

Immunogenicity 

(seroconversion to 

9vHPV types)

1091 (1)

Girls and boys 

2 doses (M 0, 6 or 12) and

Girls 

3 doses (M 0, 2, 6)

≥99.2% seropositive at 1 month post last dose in 

all groups in the per-protocol population

Immunogenicity 

(GMTs for 

9vHPV types)

549 (1)

Girls 

2 doses (M 0, 6) versus 

Girls

3 doses (M 0, 2, 6)

Lower GMTs in 2-dose group for 4/9 9vHPV

types at 1 month post last dose

544 (1)

Girls and boys

2 doses (M 0, 12) versus 

Girls

3 doses (M 0, 2, 6)

Lower GMTs in 2-dose group for 1/9 9vHPV

types at 1 month post last dose

4vHPV

Immunogenicity 

(seroconversion to 

4vHPV types)

790 (2)

Girls 

2 doses (M 0, 6) and 

Girls 

3 doses (M 0, 2, 6)

≥97.1% seropositive at 1 month post last dose in 

all groups in the per-protocol population

Immunogenicity 

(GMTs for 

4vHPV types)

495 (1)

Girls 

2 doses (M 0, 6) versus 

Girls

3 doses (M 0, 2, 6)

Non-inferiority met for 3/4 4vHPV types (but not 

HPV 18) by M 18; non-inferiority met for 2/4 

4vHPV types (but not HPV 6 or HPV 18) by M

36

295 (1)

Girls 

2 doses (M 0, 6) versus 

Girls

3 doses (M 0, 2, 6)

Non-inferiority met for 2/4 4vHPV types (but not 

HPV 6 or 18) at M 7; non-inferiority met for all

4vHPV types at M 21

2vHPV

Immunogenicity 

(seroconversion to 

2vHPV types)

1533 (2)

Girls 

2 doses (M 0, 6) and 

Girls 

3 doses (M 0, 1, 6)

100% seropositive at 1 month post last dose in all 

groups in the per-protocol population

Immunogenicity 

(GMTs for 

2vHPV types)

1384 (1)

Girls 

2 doses (M 0, 6) versus 

Girls

3 doses (M 0, 1, 6)

GMT ratios lower in 2-dose group but noninferiority met for both 2vHPV types at M 21

GMTs, Geometric Mean Titers; M, months after dose 1

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Table 6. Summary of evidence for a 2-dose schedule of HPV vaccine

Comparison Outcome

Study design

(number of studies) Findings

Evidence 

type

Overall

evidence type

2 doses of 

HPV vaccine 

(age 9–14 

years)

versus

3 doses of 

HPV vaccine 

(age 15–26 

years)

Immunogenicity,

9vHPV types Observational (1) Non-inferior immunogenicity 3

3 Immunogenicity,

4vHPV types Observational (2) Non-inferior immunogenicity 3

Immunogenicity,

2vHPV types Observational (4) Non-inferior immunogenicity 3

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Table 7. Considerations for formulating recommendations for a 2-dose schedule of HPV vaccine

Key factors Comments

Balance of benefits 

versus harms 

• If benefits are expected to be similar and the potential adverse events are 

lower, then the balance of benefits over harms is greater

Evidence type for 

benefits and harms

• GRADE evidence type 3

Values and preferences • ACIP HPV Work Group placed high value on programmatic considerations as 

well as prevention of outcomes due to vaccine-type HPV

Cost-effectiveness • Likely cost-effective compared with 3 doses

Summary

• Category A recommendation for a 2-dose schedule of HPV vaccine for girls 

and boys who initiate the vaccination series at ages 9 through 14 years

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Summary

After reviewing the available data, including the result of the GRADE analysis, ACIP voted in October 

2016 to recommend a 2-dose schedule of HPV vaccine for girls and boys who initiate the vaccination 

series at ages 9 through 14 years (Category A recommendation). See Use of a 2-Dose Schedule for 

Human Papillomavirus Vaccination — Updated Recommendations of the Advisory Committee on 

Immunization Practices.

(https://www.cdc.gov/mmwr/volumes/65/wr/mm6549a5.htm?s_cid=mm6549a5_w.(14)

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